Schizophrenia

Concurrently, neuropathologists had difficulty identifying a pathognomonic lesion for schizophrenia, compared to the successes in disorders such as Alzheimer's ...

Schizophrenia What is schizophrenia?  Definition, pros and cons  Core symptoms, other features Kraepelin’s dementia praecox Early 1800’s, not much of a language for describing mental illness, odd behaviour was the property of being possessed by the devil, and people were thrown into asylums. In the late 1800s/early 1900s, doctors tried to understand what was going on. Kraeplin drew a distinction between manic depressive illness and dementia praecox – dementia as a deterioration of the mind, praecox meaning early onset. He was a contemporary of Alzheimer so was influenced by him. Kraepelin is credited as the first to have described what we now think of as schizophrenia. He did this based on description of symptoms and course, thus laying the foundation for descriptive psychiatry. Dementia praecox essentially means “premature dementia”. This highlights what he thought of as two cardinal features of the illness - early onset and deteriorating course. This was used to distinguish schizophrenia from “manic-depressive illness” (now known as bipolar disorder), which Kraepelin believed had a fluctuating course. Bleuler’s schizophrenia Said that not everyone gets worse, there is more heterogeneity, but also a certain set of symptoms that are seen in all cases: clear cut splitting of psychic functions. Primary symptoms (define schizophrenia) and accessory symptoms (may or may not occur). Primary symptoms [4 A’s]: loosening of associations, ambivalence, autism (meaning difficult engaging/socially interaction), and affective disturbance. Bleuler recognised that not all forms the illness had an early onset. He also recognised that not all patients had a deteriorating course. He thus viewed the name ‘dementia praecox’ as inappropriate and coined the name schizophrenia, meaning ‘split mind’. Note that many of Kraepelin and Bleuler’s patients are likely to have suffered from a different illness – encephalitis lethargica (also called von Economo disease). This would have coloured their observations and biased them towards thinking that the disorder had a degenerating course. Descriptive psychiatry: look at patient’s symptoms, describe them, find regulatories, define disease categories. Emerged in parallel with psychodynamic theories. No widely accepted system. In the 1970’s a cross national study looked at two clinical settings (NY & London), compared diagnoses made by doctors to a team of doctors on the project, and found that wide variation, driven by personal preference of doctors. Triggered an effort to get more systematic about diagnosing mental disorders. Schneider’s first-rank symptoms Described different symptoms Differentiation between first-rank (core features) and second-rank (accessory) symptoms First-rank symptoms: 1. Auditory hallucinations (hearing things that aren’t there) 2. Passivity experiences (feeling you are not in control of yourself) 3. Thought echo

Second-rank symptoms: 1. Other disorders of perception 2. Sudden delusional ideas 3. Perplexity 4. Depressive/euphoric mood changes 5. Emotional impoverishment Eventually… DSM-III First attempt at a consensus diagnosis, for many disorders including schizophrenia. Kraepelin’s, Blueler’s and Schneider’s ideas were largely the basis for DSM-III criteria (1987), which represented a significant shift from theory-based to description-based diagnoses. DSM-IV criteria Characteristic symptoms: 2+ present for a significant portion of time over 1 month period 1. Delusions – fixed and erroneous belief about the world that is resistant to evidence on the contrary 2. Hallucinations – perceive something that isn’t there 3. Disorganized speech 4. Disorganized/catatonic behaviour 5. Negative symptoms: e.g. avolition, amotivation apathy, ahedonia 3+4 are features of thought disorder, what they are saying don’t make sense, loose associated between ideas. (only 1 required if delusions are bizarre [no basis in reality] or hallucinations give running commentary [voices in head] or comprise >1 voice)  Symptoms must cause social/occupational dysfunction  Continued disturbance >6 months (otherwise diagnose as schizophreniform)  Cannot be explained by drugs or other medical/psychiatric condition Subtypes (removed from DSM-V) - Paranoid - Disorganized - Catatonic - Undifferentiated - Residual Epidemiology • Lifetime prevalence of around 0.7% of the world’s population • Peak age of onset in young adulthood, typically 14-28 years (earlier in males) • Rates are higher in males early on but equivalent once risk period had ended • Rates vary with latitude, higher in countries further from the equator • Some evidence that it is higher in urban compared to rural areas • 1/3 get better, 1/3 stay the same, 1/3 get worse – contradict Kraeplin’s original ideas

Causes  Role of dopamine dysregulation Lidz and schizophrenogenic parenting Believed that early interaction (family) played an important role. Lead to a culture of blaming the parents, and the idea of a schizophrenogenic mother. May play a role in triggering relapse, but not clear whether it triggers onset. Kraeplin: Need to understand what is going on in the brain (influence by Alzheimer). Concurrently, neuropathologists had difficulty identifying a pathognomonic lesion for schizophrenia, compared to the successes in disorders such as Alzheimer’s disease In the 70’s, neuropathologists (cutting up brains) couldn’t find a clear cut signature. Corselis: present methods are not adequate to demonstrate mental aberrations that make up functional psychoses. Arvid Carlsson: 2000 Nobel Prize Winner Discovered that DA is a neurotransmitter. Showed reserpine (drug) depleted DA levels and affected motor control First to suggest that antipsychotics may act by blocking DA signaling. Seeman and Lee (1975) landmark study: Took drugs that showed efficacy in treating psychotic symptoms, and found that the dose needed correlated with how effective it was in blocking DA receptor in the striatum (in rats). More effective drugs need a smaller dose. Also discovered that people who had taken a lot of amphetamine/cocaine developed psychotic symptoms, and these are known to impact dopamine system, and if you give psychotic people these drugs it makes the symptoms worse. First brain imaging studies: Ingvar & Franzen: SPECT (precursor to PET). Inject people with radioactive tracer, found reduced blood flow in prefrontal lobes, suggesting brain disturbance. Johnstone, Crow, Frith and Husband: Compared brain structure (not function) using CT, found enlarged ventricles (fluid filled spaces in the centre of the brain) in schizophrenic patients. However this is very nonspecific. Franz Kallmann: Genetic basis A genetic influence on schizophrenia had been known for some time. One of the earliest twin studies was conducted by Franz Kallman, a German psychiatrist who left Nazi Germany for the US in 1936.  Higher concordance rate between MZ twins Franz was a student of Ernst Rudin, the Nazi psychiatrist who was a major proponent of eugenics, and had made public speeches advocated the sterilization of relatives of people with schizophrenia. These associations tainted research into the genetic basis of mental disorders. Nonetheless, the evidence from family, twin and adoption studies accumulated, and it gradually became clear that there was a strong link between genetic relation to a patient and risk of illness.

Genetic risk is not driven by any single gene: In general, genetic liability for schizophrenia seems to involve: 1 – the cumulative effect of many (100s, possibly 100s) common risk variants (i.e., inheriting a particularly bad combination of common variants); and/or 2 – the impact of large-effect but rare copy number variants (CNVs) Genes are not the whole story though, as MZ co-twins only show ~50% concordance. Weinberger (1987), and Murray and Lewis (1987) independently proposed that schizophrenia may be a neurodevelopmental disorder – i.e., that some early insult (genetic or otherwise) interacts with later maturational processes in leading to disease onset.  Weinberger proposed this model based largely on neuropathological grounds – though brain changes were notable, there was no evidence of gross degenerative changes (e.g., gliosis). - “All the biological data is consistent with a neurodevelopmental role in which a fixed lesion from early in life interacts with normal brain maturation events which occur much later” - Links to peak onset in early adolescence/early adulthood when certain systems are coming online.  Murray and Lewis proposed the view based on epidemiologic evidence of an association between pregnancy/obstetric complications and disease risk. Early neurodevelopment  Role of early neurodevelopmental factors Basic model: 1. Things going on early in life that create a vulnerability in the brain 2. This affects development 3. This interactions with brain maturation and environmental factors in adolescence, triggers onset of the illness.

Timeline of features: Typically start to see cognitive, motor and social impairments early on. Social adversity in adolescence. Prodrome (doesn’t always happen): start to feel that something is wrong, transitions into psychosis. Varied length of time for prodrome.

Risk factors

A number of non-genetic risk factors have been identified – some affect early neurodevelopment, others affect late brain development. Any combination of these with an inherited liability may be sufficient to cause disease onset. Early risk factors are all fairly generic insults to the brain, and are risk factors for other things too. Maybe create an early change that creates a general vulnerability that interacts with other factors. (Toxoplasmosa Gondii is a bacteria most commonly found in cat faeces) (Obstetric complication are at birth) (Agonism: blocks DA/NMDAR) Early evidence for influence of early risk factors on the brain from twin studies. Identical twins, one had schizophrenia, so differences were caused by environment. Smaller hippocampus in affected twin, plays a role in learning and memory but also sensitive to environmental insults.  A later study found that people who had suffered obstetric complications (trauma at labour) also tended to have smaller hippocampi. May be the site of early susceptibility.  Also showed a strong correlation between size of hippocampus and activity in prefrontal cortex (one of the first brain imaging findings). The prefrontal cortex is one of the last brain regions to develop, maturing throughout adolescence and early adulthood, suggesting a link between early and later brain development. Developed an animal model: Lesioned hippocampus in rats, shortly after birth. Followed them into adolescence, and looking at integrity of neurons in PFC. Lesioned animals showed reduced neuronal integrity, but only in adolescence. Consistent with the hypothesised timing of brain changes in schizophrenia. BUT… Many more brain regions than hippocampus and prefrontal cortex show abnormalities in schizophrenia.

Time course of brain development Born with as many neurons as you are going to have, you don’t generate new ones. The connections between the neurons change a lot – form synapses at different rates in different systems. They then get pruned. Synaptic pruning and in particular myelination continue through the teens and early adulthood, especially in prefrontal cortex. Axons connecting different areas are also myelinating: speeds up connection. These changes can be mapped with MRI: - Brain volume doesn’t change, but less grey matter  - Last region to develop is PFC, consist with idea that it matures around schizophrenia onset. Something going wrong in pruning process? One potential late neurodevelopmental mechanism leading to schizophrenia may be excess pruning—a putative “second hit”. Strategies for identifying proximal brain changes: - Study first episode patients - Perform longitudinal analyses - Study high-risk samples

One useful strategy, pioneered in Melbourne, has been to identify young people at high-risk for psychosis (people in the prodrome). They are scanned at baseline and then followed-up to determine who develops psychosis vs who does not. By comparing brain scans before and after onset, we can identify the brain changes associated with psychosis onset. In this case, the onset of psychosis is associated with increased reduction of grey matter volume in the prefrontal cortex. We can also follow patients longitudinally following disease onset to see what psychosis does to the brain in the first few years of illness.  Find a similar pattern. Suggests excess pruning in PFC. Risk-related changes may only be expressed during certain developmental windows.  Compared to controls, unaffected relatives show early changes similar to those seen in patients, but these changes disappear by adulthood. Thus, adolescence may present a specific developmental window of risk. Can use these brain changes to develop predictive markers. Initial study found that they could determine who would develop to psychosis with 82% accuracy. BUT… MRI changes are relatively non-specific, making it difficult to link the anatomical changes to modifiable mechanisms. Need to be mindful of what we are measuring. MRI is an image, made up of voxels, each of which has a different colour, reflective of the signal detected (the amount of hydrogen atoms – typically more in white matter than grey matter). Grey matter volume is inferred from this… therefore not very specific. Hard to know what is driving those changes, each voxel contains around 20-30 thousand neurons, 1 billion synapses, 4km of axons, 0.4km of dendrites. Can we identify a biological mechanism that leads to disease onset? Dopamine dysregulation seems to be a final common pathway leading to psychosis onset. What does dopamine do… Dopamine is created by neurons in the substantia nigra and ventral tegmental area of the midbrain. - These neurons fire when predicting a reward, or receiving an unexpected reward. - They are silent when a predicted reward is withheld (prediction error) Thus, DA seems to signal prediction errors. Tell us our expectations of the world are incorrect and we need to update them. These serve as a teaching signal and play a critical role in associative learning. In patients with schizophrenia, VTA neurons show excess firing to irrelevant stimuli and less firing to relevant stimuli. Everything becomes salient, everything grabs your attention.

The idea is that the dopamine system is responding to the wrong things, causes patients to focus on everything  a very strange experience of the world, the mind has to start coming up with reasons why (delusional interpretations). Dopamine in psychosis The midbrain sends strong dopaminergic projections to the striatum, the input structure of the basal ganglia. The striatum also plays a major role in prediction error signaling.  Striatal DA can be readily measured using Positron Emission Tomography (PET) [injecting radioactive tracers]. PET studies show that F-DOPA, a marker of DA synthesis capacity, is increased in patients with schizophrenia an high-risk individuals, and that these increases correlate with psychosis severity. They also predict which high-risk individuals transition to psychosis, only people with this increases develop psychosis. Correlates with severity of symptoms. The increases are particularly pronounced in the dorsal, so-called associative striatum. This part of the striatum projects to the dorsolateral prefrontal cortex, implicated as dysfunctional in structural imaging studies. We can directly test interactions between these regions by measuring correlations in their activity fluctuations over time—so-called functional connectivity. - Patients (an unaffected first-degree relative) with first episode psychosis show prominent functional connectivity reductions between dorsal striatum and dorsal prefrontal cortex. - These reductions also correlate with more severe psychosis. - Same area of striatum that shows increased dopamine. Increased dopamine has knock on effects in PFC. Models of dopamine dysregulation in psychosis

The neural circuitry of schizophrenia involves more than just two regions. It likely reflects a complicated disturbance of inhibitory, excitatory and modulatory signalling across different corticosubcortical circuits.

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